DENGUE & DENGUE

HEMORRHAGIC FEVER
Kuliah Blok Kedokteran Tropis

INTRODUCTION
Dengue is a viral infection transmitted by mosquitoes, mainly the
Aedes aegypti species.
The virus is contracted from the bite of a striped Aedes aegypti
mosquito that has previously bitten an infected person. One
mosquito bite can inflict the disease.
There are four strains or serotypes of dengue virus namely DEN-1,
DEN-2, DEN-3 and DEN-4.
The mosquito flourishes during rainy seasons but can breed in
water-filled containers, year-round.
The virus is not contagious and cannot be spread directly from
person to person. There must be a person-to-mosquito-to-another-
person pathway.
Dengue haemorrhagic fever severe form of dengue. A second
attack by dengue virus of a different serotype from the first
infection.
Approximately 1% of patients with dengue infection
progress to dengue haemorrhagic fever.
Dengue fever
Main hosts- non human
primates
Human-to-human
transmission through
Aedes spp.
2.5 billion individuals at
risk
40-80 million infected
each year with thousands
of deaths

Causative agent of Dengue
Dengue is cause by a RNA virus
This virus is a member of the viral family
Flaviviridae.

Dengue virus



Bauman, R., (2006). Microbiology disease by systems. San Francisco , CA:
Pearson Benjamin Cumming Publishers

Dengue Virus
1. Causes dengue and dengue hemorrhagic fever
2. It is an arbovirus
3. Transmitted by mosquitoes
4. Composed of single-stranded RNA
5. Has 4 serotypes (DEN-1, 2, 3, 4)

Dengue Virus
Each serotype provides specific lifetime immunity,
and short-term cross-immunity
All serotypes can cause severe and fatal disease
Genetic variation within serotypes
Some genetic variants within each serotype appear
to be more virulent or have greater epidemic potential

WHY IS DENGUE SUCH A BIG
PROBLEM TODAY?

Global population
growth
Rural to urban
migration
Growth of cities
Deterioration of
cities

Jet travel
Health services
poorly organized/
underfunded
Lack of vector
control
professionals
Global Spread of Dengue
Countries with active dengue +
Aedes aegypti
50-100 million infections/year
WORLD-WIDE DENGUE
DISTRIBUTION
Geography distribution of
Dengue





BBB
Blue dot: Geographic extension of dengue 2000-2007
Blue shaded areas: Risk of dengue transmission
Lines: Lines demarcate the area where the vector for dengue exists
VHF and other
infectious diseases
travel quickly
nowadays
Number of DHF Cases and Infected Areas
in Indonesia (1968 2003)
I
R

p
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r

1
0
0
,
0
0
0

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Incidence Rate (IR)
No of Infected Areas
Number of reported cases and deaths of DF/DHF
in Indonesia (1985-2001*)
0
1,000
2,000
3,000
4,000
5,000
6,000
7,000
8,000
1
9
8
5
1
9
8
6
1
9
8
7
1
9
8
8
1
9
8
9
1
9
9
0
1
9
9
1
1
9
9
2
1
9
9
3
1
9
9
4
1
9
9
5
1
9
9
6
1
9
9
7
1
9
9
8
1
9
9
9
2
0
0
0
2
0
0
1
*
C
a
s
e
s

(
x
1
0
)
0.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
4.00
4.50
5.00
C
F
R

(
%
)
Cases ( x10) Deaths CFR (%)
Dengue (DHF)
Outbreak in
Indonesia (2004)
Outbreak areas
Potential Outbreak areas
The most common epidemic vector of dengue in the world is
the Aedes aegypti mosquito. It can be identified by the white
bands or scale patterns on its legs and thorax.
Aedes aegypti
Dengue transmitted by infected female
mosquito

Primarily a daytime feeder

Lives around human habitation

Lays eggs and produces larvae
preferentially in artificial containers

Aedes aegypti life cycle





2-7 days


>4 days
2 days

1.The virus is inoculated into
humans with the mosquito
saliva.

2.The virus localizes and
replicates in various target
organs, for example, local
lymph nodes and the liver.

3.The virus is then released
from these tissues and
spreads through the blood to
infect white blood cells and
other lymphatic tissues.

4.The virus is then released
from these tissues and
circulates in the blood.


5.The mosquito ingests blood containing the virus.

6.The virus replicates in the mosquito midgut, the ovaries,
nerve tissue and fat body. It then escapes into the body
cavity, and later infects the salivary glands.

7.The virus replicates in the salivary glands and when the
mosquito bites another human, the cycle continues.

The transmission cycle of dengue virus by the mosquito Aedes aegypti begins
with a dengue-infected person. This person will have virus circulating in the
blooda viremia that lasts for about five days. During the viremic period, an
uninfected female Aedes aegypti mosquito bites the person and ingests blood
that contains dengue virus. Although there is some evidence of transovarial
transmission of dengue virus in Aedes aegypti, usually mosquitoes are only
infected by biting a viremic person.
Then, within the mosquito, the virus replicates during an extrinsic incubation
period of eight to twelve days.
The mosquito then bites a susceptible person and transmits the virus to him or
her, as well as to every other susceptible person the mosquito bites for the rest of
its lifetime.
The virus then replicates in the second person and produces symptoms. The
symptoms begin to appear an average of four to seven days after the mosquito
bitethis is the intrinsic incubation period, within humans. While the intrinsic
incubation period averages from four to seven days, it can range from three to 14
days.
The viremia begins slightly before the onset of symptoms. Symptoms caused by
dengue infection may last three to 10 days, with an average of five days, after the
onset of symptomsso the illness persists several days after the viremia has
ended.
Population
Infection
Clinical Cases
DHF/DSS
Asymptomatic
Infection
DF
(non-DHF)
survive
Death
5%
24%
6%
0.8%
76%
94%
99.2%
Fig. 1 Rates in dengue model
by Shepard et al. Vaccine. 2004, 22:1275-1280.
Halstead SB et al. Am J Trop Med Hyg 1969, 18:997-1021.
Age-specific DHF/DSS hospitalization in children and infant.
There are actually four dengue clinical
syndromes:
1. Undifferentiated fever;
2. Classic dengue fever;
3. Dengue hemorrhagic fever, or DHF; and
4. Dengue shock syndrome, or DSS.
Dengue shock syndrome is actually a severe
form of DHF.
Clinical Case Definition for Dengue Fever
Classical Dengue fever or Break bone fever is an acute febrile
viral disease frequently presenting with headaches, bone or joint
pain, muscular pains,rash,and leucopenia
Clinical Case Definition for Dengue Hemorrhagic Fever
4 Necessary Criteria:
1. Fever, or recent history of acute fever
2. Hemorrhagic manifestations
3. Low platelet count (100,000/mm3 or less)
4. Objective evidence of leaky capillaries:
elevated hematocrit (20% or more over baseline)
low albumin
pleural or other effusions

DENGUE
FEVER
Incubation period = 5 days
Fever = 5 days
Leukopenia
Moderate thrombocytopenia
Simmons et al
Phil J Sci 44:1-252, 1931
Clinical Manifestations- DF
IP of 2 7 days - typical patient develops
Sudden onset of fever, chills, headache
Back pain with severe myalgia, arthralgia
Retro-orbital pain break bone fever
Macular rash in axillary area
Adenopathy, palatal vesicles, scleral inj.
Maculo-papular rash on trunk
extremities
Epistaxis and scattered petechiae

Other manifestations- DF
Anorexia. Nausea, vomiting
In apparent illness-to acute incapacitation
Illness is about 25 days, biphasic course
Pain on eye movements
Pain on palpating abdominal muscles
Primarily not a respiratory illness
Rare - aseptic meningitis
Complete recovery is the rule - asthenia
Treatment of DF
Supportive measures - Vector barrier
Avoid Aspirin and if possible NSAIDs
Steroids should not be used
Fluid replacement to avoid hemoconc.
Children below 12 require careful watch
for DHF / DSS
No antiviral agents are of proven value
DISEASE SPECTRUM

MILD SEVERE

DF DHF
+ Thrombocytopenia +++ Thrombocytopenia
Hidden Vasc. Perm
1
? Overt Vasc. Perm.

1. Wills BA et al J Infect Dis 190:810-818, 2004
DENGUE HEMORRHAGIC
FEVER/DENGUE SHOCK
SYNDROME (DHF/DSS)

Dengue vasculopathy
Dengue Haemorrhagic Fever
(DHF)
Vascular instability
Decreased vascular integrity
Assault on macro vasculature
Decreased platelet function
Increased vascular permeability
Vascular disruption and local bleeds
Hypotension, hemoconcentration- shock


Criteria for DHF
Fever, or recent history of acute fever
Hemorrhagic manifestations
Low platelet count (100,000/mm
3
or
less)
Objective evidence of leaky capillaries:
Elevated hematocrit -20% or more
more over baseline or 50%
Low albumin, pleural effusion
Four Grades of DHF
Grade 1
Fever and nonspecific constitutional symptoms
Positive tourniquet test is only hemorrhagic
manifestation
Grade 2
Grade 1 manifestations + spontaneous bleeding
Grade 3
Signs of circulatory failure (rapid/weak pulse,
narrow pulse pressure, hypotension,
cold/clammy skin)
Grade 4
Profound shock (undetectable pulse and BP)

DHF Clinical Criteria
This thermometer illustrates the developments in the illness that are
progressive warning signs that DSS may occur.
The initial evaluation is made by determining how many days have passed
since the onset of symptoms.
Most patients who develop DSS do so 3-6 days after onset of symptoms.
Therefore, if a patient is seven days into the illness, it is likely that the worst
is over.
If the fever goes between three and six days after the symptoms began, this is
a warning signal that the patient must be closely observed, as shock often
occurs at or around the disappearance of fever.
Other early warning signs to be alert for include a drop in platelets, an
increase in hematocrit, or other signs of plasma leakage.
If you document hemoconcentration and thrombocytopenia and other signs
of DHF and the patient meets the criteria for DHF, the prognosis and the
patient's risk category have changed. Though dengue fever does not often
cause fatalities, a greater proportion of DHF cases are fatal.
The next concern would be observation of the danger signssevere
abdominal pain, change in mental status, vomiting and abrupt change from
fever to hypothermia. These often herald the onset of DSS.
The goal of treatment is to prevent shock. The plasma leakage syndrome is
self-limited. If you can support the patient through the plasma leakage phase
and provide sufficient fluids to prevent shock, the illness will resolve itself.

Hemorrhagic Manifestations of Dengue
Skin hemorrhages:
petechiae, purpura, ecchymoses
Gingival bleeding
Nasal bleeding
Gastrointestinal bleeding:
Hematemesis, melena, hematochezia
Hematuria
Increased menstrual flow

Clinical tests for DHF
Petechiae after tourniquet test
Overt bleed from previous GI lesions
Platelet count less than 100,000/ul
Low pulse pressure, cyanosis, effusions
Hypotension, Shock
Tourniquet Test
Inflate blood pressure cuff to a point
midway between systolic and diastolic
pressure for 5 minutes

Positive test: 20 or more petechiae
per 1 inch (6.25 cm)




Tourniquet Test
Hemorrhagic Manifestations
Skin hemorrhages:
petechiae, purpura, ecchymoses
Gingival bleeding
Nasal bleeding
Gastro-intestinal bleeding:
hematemesis, melena, hematochezia
Haematuria
Increased menstrual flow





Petechiae
Danger Signs in Dengue Hemorrhagic
Fever
Abdominal pain - intense and sustained
Persistent vomiting
Abrupt change from fever to hypothermia,
with sweating and prostration
Restlessness or somnolence

*All of these are signs of impending shock and
should alert clinicians that the patient needs close
observation and fluids.
Clinical Case Definition for Dengue Shock Syndrome
4 criteria for DHF
+
Evidence of circulatory failure manifested indirectly by
all of the following:
Rapid and weak pulse
Narrow pulse pressure (< 20 mm Hg) OR
hypotension for age
Cold, clammy skin and altered mental status
Frank shock is direct evidence of circulatory failure

DSS GRADE III
Criteria for DSS
The four criteria of DHF
Evidence of circulatory failure
1. Rapid and weak pulse
2. Narrow pulse pressue (less than 20mm)
3. Hypotension for the age
4. Cold clammy skin
5. Altered mental status
Four Grades of DHF/DSS
Grade 1
Fever, Const. Symptoms, +ve tourniquet test
Grade 2
Grade 1 + Spontaneous bleeding
Grade 3
Signs of circulatory failure
Grade 4
Profound shock - B.P. Pulse not recordable
Capillary Damage
Ecchymosis Periorbital
Edema
Large Subcutaneous Bleed
PEI = A / B x 100
Pleural Effusion
DSS GRADE IV
dengue tourniquet test
DHF
DHF / DSS
Intensive Care
Oxygen
Rehydration
Barrier Nursing
Mosquito Screen
DHF- Poor Prognostic Signs
Girl children under 12 with DHF/DSS
Severe hypotension and shock
Multifocal bleeding abdominal pain
CNS encepahlopathy, fits, coma
Watch for preorbital edema, proteinuria
postural or otherwise hypotension
Serotype 2 infection after type 4
Malnutrition is protective

Management of DHF/DSS
Close monitoring of hypotension/shock
Oxygen administration
IV. Infusion of crystalloids/colloids
Platelet transfusion
Clotting factors replacement
Case fatality is 5% in good centers
Fluid Balance
Continue monitoring after defervescence
Serial hematocrits, BP, Urine output
Fluid replacement is twice the requirement
1500 ml + 2 x (weight-20) for 60 kg wt.
Eg. {1500 + 2 x (60-20)} x 2
= {1500 + (2x 40)} x 2 = (1500 + 800) x 2
= 2300 x 2 = 4600 ml = 10 pints

Unusual Presentations of
Dengue
Encephalopathy
Hepatic damage
Cardiomyopathy
Severe GI bleeding
Signs and Symptoms of
Encephalitis/Encephalopathy Associated with
Acute Dengue Infection
Decreased level of consciousness:
lethargy, confusion, coma
Seizures
Nuchal rigidity
Paresis

Differential Diagnosis
FM complex
1. Anicteric leptospirosis
2. Rickettsial fevers
3. Influenza, Measles, Rubella
DHF / DSS
1. Other hemorrhagic fevers
2. DIC due to septicemia
3. Complicated Malaria
4. Meningococcemia
Laboratory Diagnosis
Complete Blood Counts
Hematocrit
Platelet Count
Serum GOT, GPT
Serum Albumin
Proteinuria, hematuria
Immunological Tests
Chest Skiagram
Laboratory Diagnosis
Leucopenia. Thrombocytopenia
Increased SGOT, SGPT
Rising Ab titre in paired sera
Antigen detection ELISA
IgM-capture ELISA within few hours
Reverse transcription PCR confirmatory
IgG ELISA significant of past infection


LABORATORY CRITERIA


ISOLATION OF DENQUE VIRUS
INCREASED IgM OR IgM ANTIBODIES TITRES
DENQUE ANTIGEN DETECTION BY
IMMUNOHISTOCHEMISTRY,IMMUNOFLUROSCENCE,ELISA
PCR
LEUCOPENIA,THROMPOCYTOPENIA

Immuno Detection Tests
ELISA Plate IgM-capture ELISA
Common Misconceptions- DHF
Dengue + bleeding = DHF
DHF is fatal only due to hemorrhage
No Majority of deaths are due to shock
Poorly managed DF turns into DHF
Positive tourniquet = DHF
it is not specific for DHF,
it indicates capillary fragility of any origin
More Common Misconceptions
DHF is only a pediatric illness
No, All ages may be involved
DHF is a problem of poor families
No, in fact they may not have
immune complexes to required level
Tourists will get DHF
No, in fact they are at low risk
Immunization
Each serotype produces life long immunity
There is not efficacious vaccine available
Vaccine needs to be tetravalent
Live attenuated vaccines possible
Several candidate vaccines are on trials
It may be harmful to vaccinate in view
of the pathogenesis of DHF/DSS

WHY TWO SYNDROMES,
BENIGN and SEVERE?
Observed in two immunological
settings.
1. Primary infections in infants.
2. Secondary infections in children
and adults.

PRIMARY INFECTIONS
Clinical Features

! In children
DEN 1 & 3 mild illness
DEN 2 & 4 no illness

! In adults
DEN 1 & 3 Disease/Infection ~1; g.i. hemorrhages
may accompany peptic ulcer disease.
DEN 2 & 4 - mild - moderate





Two-infections
The epidemiological data


DHF documented in children (> 1 yr)
who circulate infection-acquired
dengue antibody. Four prospective
cohort and 6 prospective
population-based studies.
In most studies, DHF comprises 2-
5% of secondary infections
DHF IN CHILDREN: PROSPECTIVE
COHORT STUDIES

References DHF/2
o
Den Inf.
DHF/1000
2
o
Den Inf.
Russell et al, AJTMH
17:600,1968
3/83 36.1
Sangawibha et al, AJE
120:653, 1984
4/112 35.7
Burke et al, AJTMH
38:172, 1988
7/59 118.6
Graham et al,
AJTMH 61:412, 1999
7/120 58.3
DHF IN CHILDREN:
PROSPECTIVE POPULATION-
BASED STUDIES
References DHF/
2
o
Den

Inf
DHF/1000
2
o
Den Inf
Halstead Acad
Press 107,1980
2528/
125,728
20.1
Russell et al AJTMH
18:600,1968
33/2700 12.2
Sangkawibha et al
AJE 120:653,1984
18/920 19.6
AJE
DHF IN CHILDREN:
PROSPECTIVE POPULATION-
BASED STUDIES
References DHF/2
o
Den Inf
DHF/1000
2
o
Den Inf
Guzman et al
AJTMH 42:179,1990
1213/
59,875
20.3
Thein et al AJTMH
56:566,1997
138/4181 33.0
Guzman et al AJE
152:793, 2000
202/4810 42.0
Established second infection
sequences leading to DHF
2 1 Thailand; Indonesia
3 1 Thailand
1 2 Cuba, 1981; Cuba 1997; Thailand
3 2 Thailand
4 2 Thailand
1 3 Cuba, 2001; Thailand; Indonesia
2 3 Thailand, DF in Cuba
1 4 Thailand
2 4 Indonesia
3 4 Thailand

Several important features of dengue disease
Dengue virus infection causes diverse disease spectrum from
mild DF to severe DHF/DSS.
Dengue disease can occur in infant, children, and adult.
Severe DHF/DSS is more prevalent in secondary infection with
different serotype of dengue virus.
Antibody-dependent enhancement is hypothesized to explain
the severe DHF/DSS in secondary infection.
Thrombocytopenia and plasma leakage are two major
characteristics of DHF/DSS.
The pathogenesis of DHF/DSS is not clearly demonstrated. The
progression from DF to DHF/DSS is not predictable.
Supportive care is the only way to treat the DHF/DSS patients.
Dengue vaccine is not commercially available yet.
DIAGNOSIS
Classic symptoms : high fever, a petechial rash with
thrombocytopenia & relative leukopenia (decrease
in the number of circulating WBC in the blood).
WHO definition of DHF :
Fever
Haemorrhagic tendency [positive tourniquet test (>
than 20 petechiae per square inch), spontaneous
bruising, bleeding from mucosa, gingiva, injection
sites, vomiting blood or bloody diarrhea].
Thrombocytopaenia [<100,000 platelets per mm].
Evidence of plasma leakage [rise in hematocrit level
> than 20%].
Serology (identification of antibodies in the blood
serum) & polymerase chain reaction (PCR) to
confirm the diagnosis of dengue if clinically
indicated.
SYMPTOMS
Sudden high fever (39-41.5C)
for 2 to 7 days
Headache
Pain behind the eyes
Muscle pain, joint pain, bone
pain (break-bone fever)
After 1 to 2 days of fever, the
patient develops initial rash
with discoloured spots, often
described as Isles of white in
a sea of red
Second rash may develop to
palms and soles, and skin
may peel off (desquamate) &
body temperature drops
TREATMENTS
No specific antiviral treatment, only supportive
treatment is given to such patients.
If the patient is dehydrating, adequate fluids are to
be taken.
Intravenous fluid is administered if the patient is
unable to maintain oral intake.
For severe body ache, painkillers may be needed.
For severe headache and for joint and muscle pain,
acetaminophen/paracetamol and codeine may be
given.
If there is significant bleeding, blood or platelet
transfusion will be carried out.

Note : Aspirin should be avoided as this drug
may worsen the bleeding tendency (because
of its anticoagulant effects & the increased
risk of developing Reye syndrome).
PREVENTIONS
STRATEGIES
Individual roles. People are urged to empty
stagnant water from old tires, trash cans &
flower pots.
Mosquito control. Place larvicide e.g. Abate or
any other suitable insecticides into any exposed
water container. Use mosquito repellant sprays
that contain NNDB or DEET.
Enforcement. Local authorities from Ministry of
Health conduct on-site check & destroy larvae
at residential premises & construction sites.
Fines may be imposed on the owner of
properties.
There is currently no vaccine available for the dengue fever.
PREVENTIONS
Fogging with insecticide. Fogging would
be carried out by local authorities in
housing area where 2 or more cases of
dengue fever are reported within one
week.
Information. In Nov 2007, the Ministry of
Health carried out a major campaign
against Aedes. During the campaign free
packages of Abate were distributed.
Leaflets & brochures to inform the public
on ways to prevent & curb Aedes breeding
are distributed.
Awareness campaign. Schools & local
communities are encouraged to carry out
communal cleaning activities. Public
awareness campaigns through
strategically placed posters & television
advertisements are also done.
Do the 10-Minute Mozzie Wipe-out everyday.
Remove water from flowerpot plates on
alternate days.
Do the 10-Minute Mozzie Wipe-out everyday.
Change water in vases on alternate days.
Do the 10-Minute Mozzie Wipe-out everyday.
Turn over all pails and water
storage containers.
Do the 10-Minute Mozzie Wipe-out everyday.
Cover bamboo pole holders
when not in use.
Do the 10-Minute Mozzie Wipe-out everyday.
Clear blockages and put Bti insecticide in roof
gutters monthly.
Unwanted items
Do not litter. Rubbish such as cups
and bottles can collect rain water
and breed mosquitoes.